Major emphasis was given to: (1) phylogenetic analysis of simian immunodeficiency virus (SIV) strains of African origin, (2) elucidation of viral determinants of SIV pathogenicity, and (3) evaluation of various SIV vaccinee strategies. An SIV isolate from a Sykes monkey was characterized and shown to be the prototype of a new, distinct primate lentivirus group. Genetic determinants of the acutely lethal SIVsm/PBj mutant were identified using chimeric viruses produced by exchange of segments of this mutant and the minimally pathogenic SIVsm H4 clone. Virulence of SIVsm/PBj is complex and multigenic, involving regions of the envelope glycoprotein (env) as well as regions of gag and/or pol. One of five full-length molecular clones of SIVsm derived from an infected monkey that developed AIDS proved to be infectious. This clone will be studied in detail during the coming year. SIVsm clones with distinct cell tropism were used to produce infectious chimeras. Analysis of these chimeras indicated that macrophage tropism resides in the V3 loop region of env. Finally, an intensive analysis of virologic and immunologic events during the very earliest stage of SIV infection in vivo was initiated. Our initial effort to develop an inactivated SIV vaccine was highly successful. Monkeys vaccinated with a psoralen-inactivated SIV suspension, derived from a proviral molecular clone, were completely resistant to challenge with homologous as well as heterologous (20% env sequence divergence) cell-free virus. IgG purified from the plasma of vaccinated monkeys protected naive monkeys from cell-free homologous SIV. However, the vaccine did not protect against challenge with cell-associated SIV but did appear to slow progression of disease.